JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis

Monica Guma, Jun Ichi Kashiwakura, Brian Crain, Yuko Kawakami, Bruce Beutler, Gary S. Firestein, Toshiaki Kawakami, Michael Karin, Maripat Corr

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease marked by bone and cartilage destruction. Current biologic therapies are beneficial in only a portion of patients; hence small molecules targeting key pathogenic signaling cascades represent alternative therapeutic strategies. Here we show that c-Jun N-terminal kinase (JNK) 1, but not JNK2, is critical for joint swelling and destruction in a serum transfer model of arthritis. The proinflammatory function of JNK1 requires bone marrow-derived cells, particularly mast cells. Without JNK1, mast cells fail to degranulate efficiently and release less IL-1β after stimulation via Fcγ receptors (FcyRs). Pharmacologic JNK inhibition effectively prevents arthritis onset and abrogates joint swelling in established disease. Hence, JNK1 controls mast cell degranulation and FcγR-triggered IL-1β production, in addition to regulating cytokine and matrix metalloproteinase biosynthesis, and is an attractive therapeutic target in inflammatory arthritis.

Original languageEnglish (US)
Pages (from-to)22122-22127
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number51
DOIs
StatePublished - Dec 21 2010

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Cell Degranulation
Interleukin-1
Mast Cells
Arthritis
Joints
Mitogen-Activated Protein Kinase 8
Biological Therapy
Fc Receptors
JNK Mitogen-Activated Protein Kinases
Matrix Metalloproteinases
Bone Marrow Cells
Cartilage
Rheumatoid Arthritis
Chronic Disease
Cytokines
Bone and Bones
Therapeutics
Serum

Keywords

  • Fcγ receptor
  • Immune complex

ASJC Scopus subject areas

  • General

Cite this

JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis. / Guma, Monica; Kashiwakura, Jun Ichi; Crain, Brian; Kawakami, Yuko; Beutler, Bruce; Firestein, Gary S.; Kawakami, Toshiaki; Karin, Michael; Corr, Maripat.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 51, 21.12.2010, p. 22122-22127.

Research output: Contribution to journalArticle

Guma, Monica ; Kashiwakura, Jun Ichi ; Crain, Brian ; Kawakami, Yuko ; Beutler, Bruce ; Firestein, Gary S. ; Kawakami, Toshiaki ; Karin, Michael ; Corr, Maripat. / JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 51. pp. 22122-22127.
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